The following description summarizes information relevant to the present invention. It is not an admission that any of the information provided herein is prior art to the presently claimed invention, nor that any of the publications specifically or implicitly referenced are prior art to that invention.
Exendins are peptides that are found in the venom of the Gila-monster, a lizard found in Arizona, and the Mexican Beaded Lizard. Exendin-3 is present in the venom of Heloderma horridum, and exendin-4 is present in the venom of Heloderma suspectum (Eng et al, J. Biol. Chem., 265:20259-20262 (1990); Eng et al, J. Biol. Chem., 267:7402-7405 (1992)). The exendins have some sequence similarity to several members of the glucagon-like peptide family, with the highest homology, 53%, being to GLP-1[7-36]NH2 (Göke et al, J. Biol. Chem., 268:19650-19655 (1993)). GLP-1[7-36]NH2, also known as proglucagon[78-107], has an insulinotropic effect, stimulating insulin secretion from pancreatic β-cells; GLP also inhibits glucagon secretion from pancreatic α-cells (Ørskov et al, Diabetes, 42:658-661 (1993); D'Alessio et al, J. Clin. Invest., 97:133-138 (1996)). GLP-1 is reported to inhibit gastric emptying (Williams et al, J Clin Endocrinol Metab., 81(1):327-332 (1996); Wettergren et al, Dig Dis Sci., 38(4):665-673 (1993)), and gastric acid secretion. (Schjoldager et al, Dig Dis Sci., 34(5):703-708 (1989); O'Halloran et al, J Endocrinol., 126(1):169-173 (1990); Wettergren et al, Dig Dis Sci., 38(4):665-673 (1993)). GLP-1[7-37], which has an additional glycine residue at its carboxy terminus, also stimulates insulin secretion in humans (Ørskov et al, Diabetes, 42:658-661 (1993)). A transmembrane G-protein adenylate-cyclase-coupled receptor believed to be responsible for the insulinotropic effect of GLP-1 is reported to have been cloned from a β-cell line (Thorens, Proc. Natl. Acad. Sci. USA, 89:8641-8645 (1992)).
Exendin-4 potently binds at GLP-1 receptors on insulin-secreting βTC1 cells, at dispersed acinar cells from guinea pig pancreas, and at parietal cells from stomach; the peptide is also said to stimulate somatostatin release and inhibit gastrin release in isolated stomachs (Göke et al, J. Biol. Chem., 268:19650-19655 (1993); Schepp et al, Eur. J. Pharmacol., 69:183-191 (1994); Eissele et al, Life Sci., 55:629-634 (1994)). Exendin-3 and exendin-4 were reported to stimulate cAMP production in, and amylase release from, pancreatic acinar cells (Malhotra et al, Regulatory Peptides, 41:149-156 (1992); Raufman et al, J. Biol. Chem., 267:21432-21437 (1992); Singh et al, Regul. Pept., 53:47-59 (1994)). The use of exendin-3 and exendin-4 as insulinotrophic agents for the treatment of diabetes mellitus and the prevention of hyperglycemia has been proposed (Eng, U.S. Pat. No. 5,424,286).
C-terminally truncated exendin peptides such as exendin[9-39], a carboxyamidated molecule, and fragments 3-39 through 9-39 have been reported to be potent and selective antagonists of GLP-1 (Göke et al, J. Biol. Chem., 268:19650-19655 (1993); Raufman et al, J. Biol. Chem., 266:2897-2902, 1991; Schepp et al, Eur. J. Pharm., 269:183-91, 1994; Montrose-Rafizadeh et al, Diabetes, 45(Suppl. 2):152A, 1996). Exendin[9-39] is said to block endogenous GLP-1 in vivo, resulting in reduced insulin secretion. (Wang et al, J. Clin. Invest., 95:417-21, 1995; D'Alessio et al, J. Clin. Invest., 97:133-38, 1996). The receptor apparently responsible for the insulinotropic effect of GLP-1 has reportedly been cloned from rat pancreatic islet cell (Thorens, Proc. Natl. Acad. Sci. USA 89:8641-8645, 1992). Exendins and exendin[9-39] are said to bind to the cloned GLP-1 receptor (rat pancreatic β-cell GLP-1 receptor (Fehmann et al, Peptides 15(3):453-6, 1994) and human GLP-1 receptor (Thorens et al, Diabetes 42(11):1678-82, 1993). In cells transfected with the cloned GLP-1 receptor, exendin-4 is reportedly an agonist, i.e., it increases cAMP, while exendin[9-39] is identified as an antagonist, i.e., it blocks the stimulatory actions of exendin-4 and GLP-1. Id.
Exendin[9-39] is also reported to act as an antagonist of the full length exendins, inhibiting stimulation of pancreatic acinar cells by exendin-3 and exendin-4 (Raufman et al, J. Biol. Chem. 266:2897-902, 1991; Raufman et al, J. Biol. Chem., 266:21432-37, 1992). It is also reported that exendin[9-39] inhibits the stimulation of plasma insulin levels by exendin-4, and inhibits the somatostatin release-stimulating and gastrin release-inhibiting activities of exendin-4 and GLP-1 (Kolligs et al, Diabetes, 44:16-19, 1995; Eissele et al, Life Sciences, 55:629-34, 1994).
Exendins have recently been found to inhibit gastric emptying (U.S. Ser. No. 08/694,954, filed Aug. 8, 1996, (abandoned, but see, U.S. Pat. No. 6,858,576) which enjoys common ownership with the present invention and is hereby incorporated by reference).
Exendin [9-39] has been used to investigate the physiological relevance of central GLP-1 in control of food intake (Turton et al, Nature, 379:69-72, 1996). GLP-1 administered by intracerebroventricular injection inhibits food intake in rats. This satiety-inducing effect of GLP-1 delivered ICV is reported to be inhibited by ICV injection of exendin [9-39] (Turton, supra). However, it has been reported that GLP-1 does not inhibit food intake in mice when administered by peripheral injection (Turton, Nature, 379:69-72, 1996; Bhavsar, Soc. Neurosci. Abstr., 21:460 (188.8), 1995).
Obesity, excess adipose tissue, is becoming increasingly prevalent in developed societies. For example, approximately 30% of adults in the U.S. were estimated to be 20 percent above desirable body weight—an accepted measure of obesity sufficient to impact a health risk (HARRISON'S PRINCIPLES OF INTERNAL MEDICINE 12th Edition, McGraw Hill, Inc. (1991) p. 411). The pathogenesis of obesity is believed to be multifactorial but the basic problem is that in obese subjects food intake and energy expenditure do not come into balance until there is excess adipose tissue. Attempts to reduce food intake, or hypernutrition, are usually fruitless in the medium term because the weight loss induced by dieting results in both increased appetite and decreased energy expenditure (Leibel et al, (1995) New England Journal of Medicine 322: 621-628). The intensity of physical exercise required to expend enough energy to materially lose adipose mass is too great for most people to undertake on a sufficiently frequent basis. Thus, obesity is currently a poorly treatable, chronic, essentially intractable metabolic disorder. Not only is obesity itself believed by some to be undesirable for cosmetic reasons, but obesity also carries serious risk of co-morbidities including, Type 2 diabetes, increased cardiac risk, hypertension, atherosclerosis, degenerative arthritis, and increased incidence of complications of surgery involving general anesthesia. Obesity due to hypernutrition is also a risk factor for the group of conditions called insulin resistance syndrome, or “syndrome X.” In syndrome X, it has been reported that there is a linkage between insulin resistance and hypertension. (Watson N. and Sandler M., Curr. Med. Res. Opin., 12(6):374-378 (1991); Kodama J. et al., Diabetes Care, 13(11):1109-1111 (1990); Lithell et al., J. Cardiovasc. Pharmacol., 15 Suppl. 5:S46-S52 (1990)).
In those few subjects who do succeed in losing weight, by about 10 percent of body weight, there can be striking improvements in co-morbid conditions, most especially Type 2 diabetes in which dieting and weight loss are the primary therapeutic modality, albeit relatively ineffective in many patients for the reasons stated above. Reducing food intake in obese subjects would decrease the plasma glucose level, the plasma lipid level, and the cardiac risk in these subjects. Hypernutrition is also the result of, and the psychological cause of, many eating disorders. Reducing food intake would also be beneficial in the treatment of such disorders.
Thus, it can be appreciated that an effective means to reduce food intake is a major challenge and a superior method of treatment would be of great utility. Such a method, and compounds and compositions which are useful therefor, have been invented and are described and claimed herein.